The overall goals of this project are to understand the role of electrical signaling in insulin secretion. We have demonstrated dramatic consequences of genetic modification of beta-cell KATP channel activity on insulin secretion and glucose tolerance: Animals with underactive KATP channels show a complex progression from hypersecretion to undersecretion and diabetes. In contrast overactive KATP channels cause undersecretion that can be severe enough to cause neonatal lethality. These animal models have both predicted and paralleled findings in humans: underactive KATP channels cause persistent hypoglycemic hyperinsulinemia, overactive KATP channels have now been shown to cause permanent neonatal diabetes. These models will allow us to examine mechanistically how imbalance in beta-cell electrical activity leads to secretory defects. This proposal will utilize a wide array of electrophysiological, transgenic, genomic and cellular biological approaches to address questions about the in vivo consequences of alterations of beta-cell electrical excitability for glucose tolerance and disease progression, both intrinsically and in response to dietary manipulations. The proposed experiments will test mechanistic hypotheses of the involvement of ion channels in stimulus-secretion coupling in beta-cells and in the etiology of hyperinsulinemia and diabetes. The results of this project will provide mechanistic information that may impact the development of new treatment approaches to both diabetes and hyperinsulinemia.